Disorders of Haemostasis (11&12) Flashcards
Defective homeostasis with abnormal bleeding is caused by:
- abnormal blood vessels
- thrombocytopenia
- disordered platelet function
- defective blood coagulation
Types of bleeding:
- vessel wall abnormalities causes low bleeding due to easy bruising and purpura (bleeding into skin and mucus membranes)
- the vascular abnormalities causes moderate bleeding due to purpura
- the coagulation abnormalities cause severe bleeding as the platelets cannot clot so bleeds in joints and tissues
Vascular bleeding disorders:
Inherited disorders:
- Hereditary haemorrhagic telangiestasia
- Connective tissue disorders
- Giant cavernous haemangioma
Characteristics: easy bruising, spontaneous bleeding even when there is no injury
Pathology: abnormality in blood vessel walls as tests come out normal so you do the tests to decide what yuou dont have
Hereditary haemorrhagic telangiestia
- uncommon (1.5 mill)
- autosomal dominant
- defects 3 genes but only caused by 1
- very thin blood vessels
- symptoms: telangiestases (dilated microvascular swellings), nose/tongue/lips, nosebleeds and GI tract blood loss (20-25%)
- increases in severity when you’re older but the incidence is decreased - usually manifests in middle-aged adults
- Treatment: embolisation, laser or transexemic acid
Causes of Acquired Vascular defects:
drug reactions steroids infections old age trauma
Purpura simplex (acquired vascular defect):
common benign disorder
occurs in women at a child bearing age
Serile purpura (acquired vascular):
old age
loss of skin elasticity, atrophy and collagen
happens in forearms, like bingo wings
Infection associated purpura (acquired vascular):
bacterial
viral (measles)
Causes of Thrombocytopenia:
- failure of platelet production (anaemia)
- increased destruction of platelets as they prematurely breakdown
- sequestration in the spleen (carries 90%)
Failure of platelet production:
- the most common cause
- bone marrow failure (aplastic anaemia or leukaemia)
- drug or viral toxicity
Diagnosis:
- clinical history
- blood film
- peripheral blood count
- bone marrow tests
Destruction of premature platelets:
- primary cause is autoantibodies attaching to platelets causing them to breakdown
- can have two autoimmune idiopathic thrombocytopenia purpura (AITP):
- chronic AITP
- acute AITP
Chronic AITP:
- common in young women
- asymptomatic
- autoantibodies in PM (IgG sensitivity by platelets)
- destroyed by macrophages in the spleen/ liver
- platelet lifespan is reduced to a few hours
Autoantibody types in chronic AITP:
glycoprotein IIb
IIa
Ib
Acute AITP:
- can lead to chronic
- in children under 10
- a viral episode can cause this (like chicken pox or measles)
- likely that IgG attaches to the viral antigen and absorbed into the platelet surface so that the autoantibodies attack the platelets
- (platelet count is less that 20 x 10^9 L)
Sequestration:
- spleen contains 30% of all platelets
- this goes up to 90%
Thrombocytopathy:
- disorder of platelet function
- count is normal
- inherited is rare
- acquired is common
Anti-platelet drugs (Acquired disorders of platelet function):
- aspirin
- irreversibly inactivate COX enzyme
- prevents production of TXA2
- inhibits platelet aggregation
- GI tract begins to bleed
- extends bleeding time and can cause haemorrhage
Haematological Malignancy (Acquired disorders of platelet function):
- acute myeloid leukaemia
- any myeloid diseases become myelomas
- some of these cells stem from platelet production
Diagnosis of disorders:
- blood count on blood film
- bone marrow biopsy
- prolonged bleeding time
- hereditary defects require further testing
Extra reading on thrombocytopenia:
- bone marrow cells become over stimulated and produce too many platelets
- TPO (thrombopoietin) triggers production
- receptor for TPO, Mpl on blood cells were examined
- identified cells that make TPO on platelets
- TPO did not act on megakaryocytes but stem cells and precursors to cause the production to go wrong
Defective Coagulation:
- inherited factors
- acquired factors
- haemophilia A/B
- vWF disease
Haemophilia A Facts:
- most common
- deficiency in factor 8 due to mutations
- 30-100 million affected
- X-linked recessive disorder
- can be spontaneous
- lots of people given blood transfusions in europe and USA were HIV positive so had acquired the disease
- all sons of an affected male will be normal
- all daughters are carriers
- all males have a defective gene
Haemophilia A clinical features:
- bleeding in joints
- haemathrosis elbow (swollen)
- pain in affected areas
- can be fatal if leads into cranial region
Haemophilia A diagnosis:
- Prolonged APTT
- confirmed factor 8 deficiency by assay
- detector by DNA analysis
- chronic biopsies at 8-10 week in utero
Symptoms of Haemophilia A:
50-100% factor conc. then no bleeding
25-50% factor conc. then severe bleeding after trauma
5-25% factor conc. then episodes after surgery or trauma
5% factor conc. then severe bleeding after slight trauma
<1% factor conc. then severe bleeding into joints after slight trauma
Treatment for Haemophilia A:
- factor 8 blood transfusion
- use DOAVP to mobilise factor 8 from endothelial cells after a minor case
- gene therapy
Haemophilia B Facts:
- X-linked recessive disorder that causes bleeding
- deficiency in factor 9 due to mutations
- 15-20 million effected
- clinically not detectable from Haem. A
Haemophilia B clinical features:
- reoccur-ant joint bleeds
- haemothrisis elbow (swollen elbows)
- bruising
- pain in affected areas
- can be fatal if in cranial regions
Haemophilia B diagnosis:
- APTT prolonged
- confirmed by factor 9 clotting assay
Haemophilia B treatment:
- factor 9 replacement by blood transfusions
vWF Facts:
- 1 in 100 asymptomatic
- clinically significant in 1 in 10,000
- autosomal dominant
- most are heterozygous
- vWF is a large protein in plasma
- promotes platelet adhesion to the damaged endothelial layer
- carrier of factor 8
vWF disease classification:
- type 1 and 3 have a partial reduction or nearly complete absence of vWF
- type 2 has an abnormal form of vWF and function
vWF disease diagnosis:
- prolonged APTT
- decreased factor 8 clotting activity
- low levels of vWF
- unpaired platelet aggregation
vWF disease clinical features:
- extent of bleeding variable
- spontaneous purpura
- severe haemorrhage following surgery
vWF disease Treatment:
- DDAOVP
- increase factor 8 and vWF with transfusion and replacement (type1 most affected)
- transexamic acid for mild bleeding
Extra reading to prove vWF disease type 2:
- mutant vWF disease mice were able to bind platelets but unable to activate them
- inhibits clot formation
Acquired coagulation disorders:
- more common than inherited
- usually multifactorial
- associated with varying assortments of platelet dysfunction and coagulation abnormalities
- vitamin k deficiency
- dissemiated (spread) intravascular coagulation
- leads to infections, trauma and sepsis (excess tissue factor made)
- coagulation produced and its inhibitors so results in no net production
- very hard to treat
A thrombus:
platelets and fibrin form a basis that forms into a blood clot in the arterial or venous ends (increased incidence with age)
An embolism:
occlusion of vessel by a foreign body (like a blood clot)
Thromboembolism:
occlusion of vessel by blood clot which has moved from its initial position
Risk factors for Thrombosis:
differ between venous and arterial
Thrombophilia:
- inherited or acquired
- predisposed to thrombosis
Virchow’s triad:
- changes in blood flow
- changes in blood constituents
- changes within walls of blood vessels
Arterial Thrombosis:
- artery + thrombus = rupture of atheroma
1. stroke
2. myocardial infarction
Stroke:
- disturbance in blood supply to the brain
- thrombotic stroke as thrombus forms around fatty plaques which leads to a block
Myocardial Infarction:
- caused by an infarct (death of tissue known as ischemia)
- obstruction of coronary artery
- if detected within 12 hours can be treated
Risk factors for Myocardial Infarction:
age
smoker
diabetes
hypertension
Venous Thrombosis (thromboembolism):
- increased systemic coagulability and stasis
- deep vein thrombosis (DVT) in the lower limbs
Symptoms of Venous Thrombosis (thromboembolism):
- swelling
- pain
- pulmonary embolism (dyspnoea, chest pain and tachpronea)
- Risk Factors of Venous Thrombosis (thromboembolism):
- Coagulation abnormality
- hereditary is factor 5 - Leiden
- can be acquired
- increased plasma levels of factor 7, 8, 9 and 11 and of fibrinogen
- lupus anticoagulant
- oral contraceptive
- malignancy
- Risk Factors of Venous Thrombosis (thromboembolism):
- Stasis
- strokes
- cardiac failure
- prolonged variability
- Risk Factors of Venous Thrombosis (thromboembolism):
- Unknown factors
- ages
- obesity
- sepsis
- NSAIDs
Inherited Thrombophilia (factor 5 Leiden) Facts:
- activated protein c resistance
- autosomal dominant
- most common to risk of thrombosis
- occurs in 5% of caucasians
- 90% of cases are a single point mutation
- arg to glu
- factor 5 is less susceptible to cleavage by protein c
Risk factors of Inherited Thrombophilia (factor 5 Leiden):
- venous stasis
- dissemiated cancer
- alterations to blood flow like AF
Therapy for Inherited Thrombophilia (factor 5 Leiden):
- anticoagulants to prevent thrombosis and stabilise clot like heparin and warfarin
- thrombolytic agents to dissolve thrombus such as plasminogen activators which convert to plasmin to break down the fibrin clot
Meds for Inherited Thrombophilia (factor 5 Leiden):
- streptokinase that activated free and fibrin bound plasminogen to release plasmin
- tissue plasminogen activator (TPA) which has a high affinity for plasmin and causes thrombinolysis
